We have been investigating the function of the ADAM15 disintegrin in the metastatic progression of human prostate cancer. This work is based on biological models of human prostate tumor growth, prostate tumor cell/vascular endothelial interactions, angiogenesis, angioinvasion and overt metastasis, which demonstrates a clear, but uncharacterized role for ADAM15 in prostate cancer progression. Our preliminary studies supports the central hypothesis that aberrant ADAM15 function in prostate tumor cells not only supports primary tumor growth, but also mediates interactions between prostate tumor cells and vascular endothelium promoting vascular intravazation and metastasis. The primary goals of this proposal will attempt to delineate the specific function of ADAM15 in these malignant processes. The mechanistically focused experiments we describe should confirm that ADAM15 functions in metastatic processes that are relevant to human prostate cancer. Consequently, this project is of direct relevance to human health. If ADAM15 can be validated as a mediator of metastatic progression of prostate cancer, then a rationale for targeting ADAM15 therapeutically would be justified. Several members of the ADAM family, including ADAM15 are emerging as regulators of the tumor microenvironment and interest in their potential as targets for the development of anticancer agents is rising. Given the diversity of ADAM15 functional domains, this disintegrin is thought to affect several important cellular processes that are intrinsic to cancer and its metastatic spread. Modalities aimed at inhibiting the extracellular activation of ADAM15 metalloproteinase activity or its EGF-homology or disintegrin domains could prove beneficial for the treatment of metastatic prostate cancer. PUBLIC HEALTH RELEVANCE: Given the diversity of ADAM15 functional domains, this disintegrin is thought to effect several important cellular processes that are intrinsic to prostate cancer and its metastatic spread. Modalities aimed at inhibiting the extracellular metalloproteinase domain, the EGF-homology domain or the disintegrin domain could prove beneficial for the treatment of metastatic prostate cancer.